The objective of the proposed research is to determine if age affects sensitivity to cytotoxic drugs. WI-38, diploid, human fibroblasts, which have been established as a model system for aging studies, or a similar strain of cells, will be used for in vitro testing of drug sensitivity. A number of drugs with different mechanisms of action will be studied to determine if certain types of damage are more lethal in senescent cells. Reproductive death as measured by generation-times and cloning ability will be the most relevant criterion for assessing the lethality of drugs in aging cells. Drugs which have cell cycle specific effects will also be tested on fibroblasts synchronized by mitotic selection. A cytolytic drug will be studied for its effects on cell growth and the release of radioactive markers of different sizes. These results will indicate whether aging of the plasma membrane labilizes it to injury by substances such as bacterial toxins. To determine the basis for sensitivity differences in aging cells, reproductive death will be correlated with metabolic death as measured by incorporation of nucleic acid and precursors into whole cells and nuclear monolayers. The uptake of drugs by diffusion and active transport in WI-38 cells of varying ages will be studied as a possible basis for sensitivity differences.